The incidence of overweight and obesity continue to escalate in all age groups of the US population. Because excess adiposity is associated with increased risk for chronic disease and mortality it is essential that we develop an understanding of the physiological mechanisms that are in place to regulate adiposity and how environmental factors can make these mechanisms ineffectual. This proposal focuses on how the adipocyte derived cytokine leptin modifies whole body energy metabolism and adipocyte metabolism. It appears that there are at least three different stages of leptin responsiveness in experimental animals treated with physiological doses of the hormone: a) leptin sensitivity that facilitates a loss of body fat in response to leptin b) partial leptin resistance that leads to an increase in adiposity in response to leptin and c) full leptin resistance that prevents any metabolic response to peripherally administered leptin. This proposal focuses on the second condition. The first Specific Aim will examine the mechanistic basis of fat gain in rats that are partially leptin resistant. The proposed studies will test the hypothesis that when peripherally administered leptin is unable to increase activity of leptin receptors located in the forebrain, but can stimulate receptors in the hindbrain and/or periphery, then there is a shift in energy balance and metabolic status that favors fat deposition. Successful completion of this Aim will determine the conditions required and mechanisms responsible for acceleration of body fat gain in conditions of partial leptin-resistance. These studies will provide important new information on how environmental factors decrease the efficacy of mechanisms responsible for the regulation of body fat content and may even promote weight gain. The second Specific Aim includes studies that will identify the location of leptin receptors responsible for the accretion of fat in partially leptin resistant animals. Successful completion of this Aim will provide opportunities to modulate activity of endogenous factors that lead to the accumulation of white fat, and thus prevent, or reverse, obesity. PUBLIC HEALTH RELEVANCE: Because excessive adiposity is associated with a significant increase in risk for a large number of chronic diseases the epidemic of obesity represents a major economic and societal burden. Studies described in this proposal will examine how leptin, a cytokine that is released from adipose tissue, promotes fat gain in conditions of partial leptin resistance. This will provide important new information on how environmental factors modify mechanisms responsible for regulating the size of body fat stores and may even promote weight gain.